ABSTRACT
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Inhaled particles impinge upon epithelial cells of the respiratory tract after inhalation, facilitating an
inflammatory response. In addition to causing epithelial cell injury through mechanisms involving
DNA damage, pathogenic particles such as silica or asbestos elicit toxic and proliferative responses
in lung cells through cell signaling pathways that can be triggered by direct interactions of fibers
with the plasma membrane (Rom et al. 1991; Adamson 1997; Mossman and Churg 1998) or
indirectly via reactive oxygen species (ROS) (Shukla et al. 2003a). At high concentrations of
particles, exposures result in cell death and repair or compensatory proliferation of surrounding
epithelial cells. If this phenomenon occurs subsequent to DNA damage, a situation could arise
whereby the replicating population, including initiated cells that have an increased propensity
towards further genetic instability, could continue on the route towards malignancy, i.e., lung
cancers. The elucidation of the molecular mechanisms of cell injury and proliferation by inhaled
particles is therefore critically important for understanding mechanisms of lung cancer and
mesothelioma, a tumor unique to asbestos fibers, as well as pulmonary or pleural fibrosis. In
these diseases, proliferation of epithelial cells or mesothelial cells may play dual roles: (1) repair
of damaged epithelium, and (2) production of cytokines and chemokines that encourage inflam-
mation and proliferation. In this chapter, we focus on cell signaling pathways controlling these
processes. Although these cascades were first characterized in epithelial and mesothelial cells after
exposure to asbestos or silica, several of these pathways have now been documented in various cell
types after exposure to airborne particulate matter (PM), diesel exhaust, and/or ultrafine particles
from a variety of sources. Because cell-signaling pathways initiated by particulates are studied in an
effort to understand how to control proliferative and inflammatory alterations intrinsic to particu-
late-associated lung diseases, we first present the relevance of these processes to the pathogenesis of
fibrogenic, carcinogenic, and inflammatory diseases such as asthma. We then describe relevant
signaling cascades impinging upon the activator protein-1 (AP-1) and nuclear factor-kB (NF-kB)
transcription factors and what is known about their activation by various particulates. Lastly, we
provide a perspective on how these pathways can be verified in lung tissue after inhalation or
instillation of particles for screening and therapy of particle-associated diseases.
